[unreadable] Abnormal liver enzymes are frequently seen in those with HIV. Although many of these individuals are co-infected with HBV or HCV, histology in HIV patients with abnormal liver enzymes in the absence of viral hepatitis has not been explored. HAART has significantly improved the survival in those living with HIV. However, components of HAART, particularly protease inhibitors (PIs) and certain nucleoside reverse transcriptase inhibitors (NRTIs), are frequently associated with metabolic abnormalities including insulin resistance (IR), dyslipidemias, fat redistribution and lipodystrophy (LD). Both IR and dyslipidemia are pathogenic mechanisms associated with nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) which often present as asymptomatic liver enzyme elevations. Because NASH is now recognized as a significant cause of cirrhosis with associated morbidity and mortality, its recognition as a long term complication of HAART is important to the management of those living with HIV. In our HIV population without HCV or HBV, there is a higher prevalence of abnormal liver enzymes (AST 21%, ALT 16%, ALP 43%) compared to the general population (ALT 8%) and is independently associated with PI use. The relationship of liver enzyme abnormalities to IR, dyslipidemias, and the development hepatic steatosis/NASH in HIV patients is unknown. We hypothesize that Liver enzyme abnormalities in HIV positive patients without viral hepatitis co-infections on HAART are due to hepatic steatosis related to PI use and that a subset of these individuals has NASH. The Specific Aims focus on HIV positive patients with abnormal liver enzymes in the absence of viral hepatitis co-infections, diabetes, or alcohol abuse to answer the following three questions: (1) What is the spectrum of NAFLD?; (2) How does the spectrum compare in those that are on a PI compare to those that are not; and (3) What are the independent predictive factors associated with hepatic steatosis and NASH? These studies will (1) provide novel data on the histology of HIV infected patients with abnormal liver enzymes in the absence of viral coinfections and their relationship to IR, LD, dyslipidemias, and HAART use and (2) provide the necessary pilot data for a multicenter R0-1 grant to study the long-term impact of HAART on the development of steatohepatitis and subsequent hepatic fibrosis. AN OVERVIEW OF THIS PROPOSAL Abnormal liver enzymes (aspartate aminotransferase: AST, alanine aminotransferase: ALT, and alkaline phophatase: ALP) are frequently seen in those with human immunodeficiency virus (HIV). Although many of these individuals are co-infected with hepatitis B virus (HBV) or C virus (HCV), histology in HIV patients with abnormal liver enzymes in the absence of viral hepatitis has not been explored. Highly active anti-retroviral therapy (HAART) has significantly improved the survival in those living with HIV. However, components of HAART, particularly protease inhibitors (PIs) and certain nucleoside reverse transcriptase inhibitors (NRTIs), are frequently associated with metabolic abnormalities including insulin resistance (IR), dyslipidemias, fat redistribution and lipodystrophy (LD). Both IR and dyslipidemia are pathogenic mechanisms associated with nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) which often present as asymptomatic liver enzyme elevations. Because NASH is now recognized as a significant cause of cirrhosis with associated morbidity and mortality, its recognition as a long term complication of HAART is important to the management of those living with HIV. In our HIV population without HCV or HBV, there is a higher prevalence of abnormal liver enzymes (AST 21%, ALT 16%, ALP 43%) compared to the general population and is independently associated with PI use. The relationship of liver enzyme abnormalities to PI use, IR, dyslipidemias, and the development hepatic steatosis/NASH in HIV patients is unknown. We hypothesize that: Liver enzyme abnormalities in HIV positive patients without viral hepatitis co-infections on HAART are due to hepatic steatosis related to PI use and that a subset of these individuals has NASH. The Specific Aims focus on HIV positive patients with abnormal liver enzymes in the absence of viral hepatitis co-infections, diabetes, or alcohol abuse to answer the following three questions: (1) What is the spectrum of NAFLD? (2) Is the prevalence and severity of NAFLD greater in those whose HAART includes PIs? (3) What are the independent predictive factors associated with NAFLD and NASH? HIV infected subjects without evidence of HCV or HBV will be screened for elevated liver enzymes and those with persistent (> 6 months) liver enzyme elevations will undergo liver biopsy as part of standard of care. In the first specific aim, the histologic spectrum of liver disease in the study population will be defined with particular attention to features of steatosis/steatohepatitis and quantified by the NIH-NASH CRN criteria. In the second aim, we will compare the spectrum of NAFLD in those on a PI compared to those who are not. In the third specific aim, a multivariable logistic regression analyses with steatosis/NASH determined by liver biopsy as the dependent variables will assess independent predictive factors associated with steatosis/NASH. These variables will include patient demographics (age, gender, race), HAART use (particularly PI vs. non-PI regimens and specific NRTI use), immune status (CD4 count and HIV RNA level), dyslipidemia, IR, body fat composition and distribution, and presence of the metabolic syndrome. These studies will (1) provide novel data on the histology of HIV infected patients with abnormal liver enzymes in the absence of viral coinfections and their relationship to IR, LD, dyslipidemias, and HAART use and (2) provide the necessary pilot data for a multicenter R0-1 grant to study the long-term impact of HAART on the development of steatohepatitis and subsequent hepatic fibrosis. This R03 application is submitted under PAR-04-070: Small Grant Program for NIDDK K08/K23 Recipients which allows for additional funding to run concurrently with the latter years of the K08/K23 award. The current proposal is related to the applicant's K23 and will allow him to conduct this pilot study to gain data to be used in a R01 application as well as to contribute to his development as an independent investigator. If our hypothesis is correct, this work could result in a dramatic change in the long-term care of the over 1 million HIV infected individuals in the US. [unreadable] [unreadable]